An important feature of infections with immunodeficiency viruses - human (HIV) or simian (SIV) - is the host failure to mount an effective immunological defense against the virus. In some individuals, a status of long-term non-progression is established. It has been suggested that gammadelta T cell- mediated immunity may influence the outcome of HIV/SIV infections. The focus of the first Specific Aim of this proposal is to assess therapeutic vaccination that stimulates gammadelta T cells and its capacity to influence a) the in vivo virus load in SIV-infected animals and b) the pace of SIV disease progression. The second Specific Aim addresses the effect of therapeutic vaccinations with nonpeptidic antigens in the context of discontinuation of highly active antiretroviral therapy (HAART). The presence of strong Vgamma9Vdelta2 T-cell activation by nonpeptidic antigens in vitro results in a potent inhibition of HIV/SIV replication; this will be used to identify the most potent nonpeptidic antigen(s) for Vgamma9Vdelta2 T-cell stimulation. The activation of Vgamma9Vdelta2 T cells will be measured in terms of their cytotoxic activities and their capacity to produce cytokines and antiviral beta-chemokines. The SIV disease progression in SIV-challenged rhesus macaques will be assessed [the immunological parameters (numbers and functions of lymphoid cells) and the in vivo virus load will be monitored using flow cytometry, ELISA and PCR techniques] before and after receiving therapeutic vaccinations with or without HAART and compared with untreated controls. Survival times will be recorded. The efficacy of the testing will be analyzed and the influence of therapeutic vaccinations on prognosis and survival in SIV-infected animals will be determined. Successful outcomes may result in novel therapeutic vaccination strategies for clinical testing in human AIDS.